Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice
- Author(s)
- Kauppi, MK; Hyland, CD; Viney, EM; White, CA; de Graaf, CA; Welch, AE; Yousef, J; Dagley, LF; Emery-Corbin, SJ; Di Rago, L; Kueh, AJ; Herold, MJ; Hilton, DJ; Babon, JJ; Nicola, NA; Behrens, K; Alexander, WS;
- Journal Title
- Blood
- Publication Type
- Dec 27 epub ahead of print
- Abstract
- Cullin-5 (Cul5) coordinates assembly of cullin-RING-E3 ubiquitin (Ub) ligase (CRL) complexes that include Suppressor of Cytokine Signaling (SOCS)-box-containing proteins. The SOCS-box proteins function to recruit specific substrates to the complex for ubiquitination and degradation. In hematopoiesis, SOCS-box proteins are best known for regulating the actions of cytokines that utilize the JAK-STAT signaling pathway. However, the roles of most SOCS-box proteins have not been studied in physiological contexts and any actions for Cul5/SOCS complexes in signaling by several hematopoietic cytokines, including thrombopoietin (TPO) and interleukin-3 (IL-3), remain unknown. To define additional potential roles for Cul5/SOCS complexes, we generated mice lacking Cul5 in hematopoiesis; the absence of Cul5 is predicted to impair the SOCS-box-dependent actions of all proteins that contain this motif. Here, we show that Cul5-deficient mice develop excess megakaryopoiesis and thrombocytosis revealing a novel mechanism of negative regulation of megakaryocyte-committed stem cells, a distinct population within the hematopoietic stem cell pool that have been shown to rapidly, perhaps directly, generate megakaryocytes, and which are produced in excess in the absence of Cul5. Cul5-deficient megakaryopoiesis is distinctive in being largely independent of TPO/Mpl and involves signaling via the beta-common and/or beta-IL-3 receptors, with evidence of deregulated responses to IL-3. This process is independent of the interferon-alpha/beta receptor (IFNARI), previously implicated in inflammation-induced activation of stem-like megakaryocyte progenitor cells.
- Publisher
- Elsevier
- Research Division(s)
- Blood Cells And Blood Cancer; Advanced Technology and Biology; Immunology
- PubMed ID
- 39791603
- Publisher's Version
- https://doi.org/10.1182/blood.2024025406
- Open Access at Publisher's Site
https://doi.org/0.1182/blood.2024025406- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-01-20 03:39:11
Last Modified: 2025-01-21 10:53:44